Adjuvant leuprolide with or without docetaxel in patients with high-risk prostate cancer after radical prostatectomy (TAX-3501): Important lessons for future trials.
ABSTRACT The current trial evaluated 2 common therapies for patients with advanced prostate cancer, docetaxel and hormonal therapy (HT), in the surgical adjuvant setting.
TAX-3501 was a randomized, phase 3, adjuvant study post-radical prostatectomy (RP) in high-risk patients with prostate cancer (n = 228) comparing 18 months of HT with (CHT) without docetaxel chemotherapy either immediately (I) or deferred (D). High-risk disease was defined as a 5-year freedom-from-disease-progression rate of ≤ 60% as predicted by a post-RP nomogram. Progression-free survival (PFS), including prostate-specific antigen disease recurrence, was the primary endpoint. The authors also assessed the accuracy of the nomogram and analyzed testosterone recovery in 108 patients treated with HT who had at least 1 posttreatment testosterone value.
Between December 2005 and September 2007, 228 patients were randomized between the treatment cohorts. TAX-3501 was terminated prematurely because of enrollment challenges, leaving it underpowered to detect differences in PFS. After a median follow-up of 3.4 years (interquartile range, 2.3-3.8 years), 39 of 228 patients (17%) demonstrated PSA disease progression, and metastatic disease progression occurred in 1 patient. The median time to baseline testosterone recovery after the completion of treatment was prolonged at 487 days (95% confidence interval, 457-546 days). The nomogram's predicted versus observed freedom from disease progression was significantly different for the combination D(HT) and D(CHT) group (P < .00001).
TAX-3501 illustrated several difficulties involved in conducting postoperative adjuvant systemic trials in men with high-risk prostate cancer: the lack of consensus regarding patient selection and treatment, the need for long follow-up time, nonvalidated intermediate endpoints, evolving standard approaches, and the need for long-term research support. Except for selected patients at very high-risk of disease recurrence and death, surgical adjuvant trials in patients with prostate cancer may not be feasible. Cancer 2013. © 2013 American Cancer Society.
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ABSTRACT: We studied 721 men with clinically confined disease who underwent radical prostatectomy. No patient received preoperative or postoperative radiotherapy or hormone therapy until progression occurred. For those men without progression, the mean follow-up was 6.5 years with a median of 6 years (range 1 to 12 years). Because patients with lymph node metastases or seminal vesicle invasion had such a high risk of progression, enhanced prognostication was not needed in men with these findings. Thus we focused this analysis on the 617 men without lymph node metastases or seminal vesicle invasion. In the multivariate analysis, Gleason score (P < 0.0001), surgical margins (P = 0.004), and capsular penetration (P = 0.007) were all independent predictors of progression. Tumors with a Gleason score of 2 through 4 were almost invariably cured, with a 10-year progression-free risk of 96%. At the opposite end of the spectrum, the 10-year actuarial progression-free risk for men with a Gleason score of 8 through 9 was 35%. Men with Gleason score 2 through 4 or 8 through 9 tumors could not be stratified into different risks of progression based on the presence or extent of capsular penetration or margin status. For the men with Gleason score 5 through 7 tumors (88.2% of cases), predicting their risk of progression was enhanced by knowledge of their tumor's capsular penetration and margin status. Tumors with a Gleason score of 5 through 6 and 7 were each stratified into three groups with different risks of progression. Using the actuarial curves within this study, physicians will be able to more accurately determine a patient's risk of progression following radical prostatectomy based on a combination of the radical prostatectomy Gleason score, extent of capsular penetration, and status of surgical margins of resection.American Journal of Surgical Pathology 04/1996; 20(3):286-92. · 4.59 Impact Factor
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ABSTRACT: Although androgen suppression results in a tumor response/remission in the majority of patients with carcinoma of the prostate, its potential value as an adjuvant has not been substantiated. In 1987, the Radiation Therapy Oncology Group (RTOG) initiated a randomized phase III trial of adjuvant goserelin in definitively irradiated patients with carcinoma of the prostate. A total of 977 patients had been accessioned to the study. Of these, 945 remained analyzable: 477 on the adjuvant arm and 468 on the observation arm. Actuarial projections show that at 5 years, 84% of patients on the adjuvant goserelin arm and 71% on the observation arm remain without evidence of local recurrence (P < .0001). The corresponding figures for freedom from distant metastases and disease-free survival are 83% versus 70% (P < .001) and 60% and 44% (P < .0001). If prostate-specific antigen (PSA) level greater than 1.5 ng is included as a failure (after > or = 1 year), the 5-year disease-free survival rate on the adjuvant goserelin arm is 53% versus 20% on the observation arm (P < .0001). The 5-year survival rate (for the entire population) is 75% on the adjuvant arm versus 71% on the observation arm (P = .52). However, in patients with centrally reviewed tumors with a Gleason score of 8 to 10, the difference in actuarial 5-year survival (66% on the adjuvant goserelin arm v 55% on the observation arm) reaches statistical significance (P = .03). Application of androgen suppression as an adjuvant to definitive radiotherapy has been associated with a highly significant improvement in local control and freedom from disease progression. At this point, with a median follow-up time of 4.5 years, a significant improvement in survival has been observed only in patients with centrally reviewed tumors with a Gleason score of 8 to 10.Journal of Clinical Oncology 04/1997; 15(3):1013-21. · 17.88 Impact Factor
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ABSTRACT: In a series of 1623 men with a follow-up of 5 +/- 3 years (range 1-13) after anatomic RRP for clinically localized prostate cancer, 17% (276/1623) have shown recurrence. A detectable PSA was the only evidence of recurrence in 7.9%, whereas 2.5% have recurred locally and 5.4% have developed distant metastases. The overall actuarial progression-free rate for these men at 10 years was 68%. Actuarial rates at 10 years were 18% for development of an isolated PSA recurrence, 8% for local recurrence, and 9% for distant recurrence. The actuarial likelihood of a postoperative recurrence increased with increasing clinical stage, Gleason score, preoperative PSA level, and pathologic stage. Although not shown in our previous report, the actuarial rate of recurrence of tumors with a Gleason score of 7 was statistically different from that of tumors of higher Gleason score (8-10). As well, men with preoperative PSA levels of 10.1 to 20 ng/mL experienced recurrence at a significantly lower rate than did men with preoperative PSA levels greater than 20 ng/mL. By using a combination of Gleason score, pathologic stage, and surgical margin status, we demonstrated that the presence of a positive surgical margin did not dramatically affect recurrence in tumors of Gleason scores 2 to 6 with capsular penetration. Surgical margin status was important in high-grade tumors with capsular penetration. In fact, tumors with capsular penetration, Gleason score of at least 7, and a positive surgical margin behaved similarly to tumors with invasion of the seminal vesicles. Preservation of potency did not adversely influence cancer control. The Gleason score, presence or absence of seminal vesicle or lymph node involvement, and the timing of PSA recurrence are all important variables in predicting eventual local versus distant failure associated with an isolated rise in serum PSA. Overall actuarial cause-specific survival at 5 and 10 years was 99% and 93%. Although there was no difference in survival among men grouped by TNM stage or preoperative PSA, advancing histologic grade and pathologic stage did have an effect on actuarial cause-specific survival. Men undergoing RRP for clinically localized prostate cancer showed a 16% actuarial rate of development of metastatic disease at 10 years. This is considerably better than conservative therapy and justifies RRP as the treatment of choice for men with clinically localized disease who are otherwise healthy and have a greater than 10-year life expectancy.Urologic Clinics of North America 06/1997; 24(2):395-406. · 1.35 Impact Factor